Genetic Variant NM_000789.4:c.41_43delTGC (chr17-63477126-GGCT-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP3

The NM_000789.4(ACE):c.41_43delTGC(p.Leu14del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000799 in 1,251,088 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 8.0e-7 ( 0 hom. )

Consequence

ACE
NM_000789.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.01

Publications

0 publications found

Variant links:

Genes affected

ACE (HGNC:2707): (angiotensin I converting enzyme) This gene encodes an enzyme involved in blood pressure regulation and electrolyte balance. It catalyzes the conversion of angiotensin I into a physiologically active peptide angiotensin II. Angiotensin II is a potent vasopressor and aldosterone-stimulating peptide that controls blood pressure and fluid-electrolyte balance. This angiotensin converting enzyme (ACE) also inactivates the vasodilator protein, bradykinin. Accordingly, the encoded enzyme increases blood pressure and is a drug target of ACE inhibitors, which are often prescribed to reduce blood pressure. This enzyme additionally plays a role in fertility through its ability to cleave and release GPI-anchored membrane proteins in spermatozoa. Many studies have associated the presence or absence of a 287 bp Alu repeat element in this gene with the levels of circulating enzyme. This polymorphism, as well as mutations in this gene, have been implicated in a wide variety of diseases including cardiovascular pathophysiologies, psoriasis, renal disease, stroke, and Alzheimer's disease. Regulation of the homologous ACE2 gene may be involved in progression of disease caused by several human coronaviruses, including SARS-CoV and SARS-CoV-2. Alternative splicing results in multiple transcript variants encoding both somatic (sACE) and male-specific testicular (tACE) isoforms. [provided by RefSeq, Sep 2020]

ACE Gene-Disease associations (from GenCC):

renal tubular dysgenesis - ACE
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
renal tubular dysgenesis of genetic origin
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
intracerebral hemorrhage
Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACE links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP3

Nonframeshift variant in repetitive region in NM_000789.4

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000789.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACE	NM_000789.4	MANE Select	c.41_43delTGC	p.Leu14del	disruptive_inframe_deletion	Exon 1 of 25	NP_000780.1	P12821-1
ACE	NM_001382700.1		c.-195_-193delTGC		5_prime_UTR	Exon 1 of 22	NP_001369629.1
ACE	NM_001382701.1		c.-574_-572delTGC		5_prime_UTR	Exon 1 of 23	NP_001369630.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACE	ENST00000290866.10	TSL:1 MANE Select	c.41_43delTGC	p.Leu14del	disruptive_inframe_deletion	Exon 1 of 25	ENSP00000290866.4	P12821-1
ACE	ENST00000953328.1		c.41_43delTGC	p.Leu14del	disruptive_inframe_deletion	Exon 1 of 25	ENSP00000623387.1
ACE	ENST00000884279.1		c.41_43delTGC	p.Leu14del	disruptive_inframe_deletion	Exon 1 of 25	ENSP00000554338.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.99e-7

AC:

AN:

1251088

Hom.:

AF XY:

0.00

AC XY:

AN XY:

613924

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

25256

American (AMR)

AF:

0.00

AC:

AN:

21916

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20172

East Asian (EAS)

AF:

0.00

AC:

AN:

26604

South Asian (SAS)

AF:

0.00

AC:

AN:

59832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3606

European-Non Finnish (NFE)

AF:

9.89e-7

AC:

AN:

1011284

Other (OTH)

AF:

0.00

AC:

AN:

51054

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over